Suzuki-Miyaura cross-coupling of 3,4-disubstituted 5-bromoisoxazoles: An efficient access to trisubstituted isoxazoles

Article abstract of DOI:10.1016/j.tetlet.2021.153185

The Suzuki-Miyaura cross-coupling of 3,4-disubstituted 5-bromoisoxazoles 1 at the C5 position has successfully proceeded in the presence of Pd₂(dba)₃ and P(t-Bu)₃·HBF₄ catalysts to give the corresponding trisubstituted isoxazoles 3 in good to high yields while suppressing the formation of ketone 4 as a byproduct. The use of bulky phosphine ligand P(t-Bu)₃·HBF₄ is essential for the current transformation, and the formation of ketone 4, which was a major product in the previous report, was able to be suppressed under the current conditions.

Full text of DOI:10.1016/j.tetlet.2021.153185

Tetrahedron Letters 75 (2021) 153185
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Suzuki-Miyaura cross-coupling of 3,4-disubstituted 5-bromoisoxazoles:
An efficient access to trisubstituted isoxazoles
Masato Tsuda a, Taiki Morita a,b, Hiroyuki Nakamura a,b,
⇑
a School of Life Science and Technology, Tokyo Institute of Technology, 4259 Nagatsuta-cho Midori-ku, Yokohama 226-8503, Japan
b Laboratory for Chemistry and Life Science, Institute of Innovative Research, Tokyo Institute of Technology, 4259 Nagatsuta-cho Midori-ku, Yokohama 226-8503, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
The Suzuki-Miyaura cross-coupling of 3,4-disubstituted 5-bromoisoxazoles 1 at the C5 position has suc-
cessfully proceeded in the presence of Pd2(dba)3 and P(t-Bu)3ꢀHBF4 catalysts to give the corresponding
trisubstituted isoxazoles 3 in good to high yields while suppressing the formation of ketone 4 as a
byproduct. The use of bulky phosphine ligand P(t-Bu)3ꢀHBF4 is essential for the current transformation,
and the formation of ketone 4, which was a major product in the previous report, was able to be sup-
pressed under the current conditions.
Received 10 April 2021
Revised 12 May 2021
Accepted 17 May 2021
Available online 18 May 2021
Keywords:
Isoxazole
Ó 2021 Elsevier Ltd. All rights reserved.
Cross-coupling
Suzuki-Miyaura
Introduction
3,4-disubstituted 5-(pseudo)halogenated isoxazole [10]. According
to their report, 3,4-disubstituted 5-bromoisoxazoles such as 1a did
Isoxazole is a five-membered heteroaromatic compound con-
taining a nitrogen–oxygen bond in its ring. The ring structure has
been recognized as a privileged framework in medicinal chemistry,
because the isoxazole ring itself exhibits critical pharmacophores
for biological activity [1]. This high utility as pharmaceuticals has
encouraged the development of various synthetic approaches
towards functionalized isoxazoles [2]. Most of them, however,
are based on conventional ring construction strategies that often
suffer from insufficient regioselectivity and poor availability of lin-
ear components. On the other hand, the direct functionalization
approach has not been established mainly due to its lability under
basic conditions. To resolve this situation, we have developed
direct functionalization methods such as 4-isoxazolyl anion spe-
cies [3], gold(I)-catalyzed SEAr type reactions,[4] and rhodium
(III)-catalyzed CAH functionalizations [5]. Turning our attention
to cross-coupling strategy which enables regioselective installation
of substituents on heteroarenes using readily available building
blocks [6]. 3,5-disubstituted isoxazoles were successfully synthe-
sized via Suzuki-Miyaura coupling (Scheme 1a) [7]. However, the
synthesis of trisubstituted isoxazoles via cross-coupling reactions
at the C5 position has not been well developed [8,9]. Furthermore,
Jurberg et al. clearly pointed out the difficulty in cross-coupling of
not participate in Suzuki-Miyaura coupling, and desired trisubsti-
tuted isoxazoles were not obtained at all (Scheme 1b). Intrigued
by their report, we decided to investigate the cross-coupling reac-
tions of 5-bromoisoxazoles 1 with aryl boronic acids 2 in detail and
succeeded in synthesizing trisubstituted isoxazoles 3 (Scheme 1c).
Results and discussion
Based on the previous report by Jurberg and coworkers, we
began with an investigation on Suzuki-Miyaura cross-coupling of
4-benzyl-5-bromo-3-phenylisoxazole (1a) and phenylboronic acid
(2a) (Table 1). First, we treated 1a and 2a in combination with Pd
(PPh3)4 (10 mol%) and Na2CO3 (4.0 equiv.) in 1,4-dioxane at 100 °C
for 16 h, as following the previously reported combination. As a
result, the desired product 3a was not observed, though the ring-
opening product 4a was obtained in 22% yield along with 15%
recovery of bromoisoxazole 1a. This ring-opening process was also
observed by Jurberg et al. when they employed isoxazolyl triflate
instead of 1a [10]. The ketone 4a was presumably given by NAO
bond cleavage of the intermediate generated via oxidative addi-
tion, followed by hydrolysis and decarboxylation [11]. Surprisingly,
by simply changing the base from Na2CO3 to K3PO4, the desired
trisubstituted isoxazole 3a was produced in 67% yield (entry 2).
In this case, ring-opening of the isoxazole ring also proceeded,
resulting in the undesired ketone 4a in a non-negligible yield
(24%). To suppress the generation of the ring-opening product 4a,
condition screening was performed. The use of Pd(OAc)2 without
⇑
Corresponding author at: Laboratory for Chemistry and Life Science, Institute of
Innovative Research, Tokyo Institute of Technology, 4259 Nagatsuta-cho Midori-ku,
Yokohama 226-8503, Japan.
E-mail address: hiro@res.titech.ac.jp (H. Nakamura).
https://doi.org/10.1016/j.tetlet.2021.153185
0040-4039/Ó 2021 Elsevier Ltd. All rights reserved.

M. Tsuda, T. Morita and H. Nakamura
Tetrahedron Letters 75 (2021) 153185
With the best conditions in our hand (Table 1, entry 7), we next
examined the scope of Suzuki-Miyaura cross-coupling of 3,4-dis-
ubstituted 5-bromoisoxazole 1a with various aryl boronic acids
(Table 2). Aryl groups having both an electron donating group (en-
try 2) and electron withdrawing groups (entries 3–6) were intro-
duced into C5 position of the isoxazole ring, and corresponding
trisubstituted isoxazoles 3b-f were provided in moderate to good
yields (52–84%). The styrene derivative 3 g was also obtained via
the cross-coupling of 1a with 4-vinylphenylboronic acid 2 g,
though the yield was rather sluggish (entry 6). Heteroaryl boronic
acids, such as 4-pyridylboronic acid 2 h and 2-thiopheneboronic
acid 2i, were coupled with substrate 1a to afford 3 h and 3i in
54% and 57% yields, respectively (entries 7 and 8). Further, the
cross-coupling using 2-naphthaleneboronic acid 2j afforded the
corresponding coupling product 3j in 92% yield (entry 9). In all
cases in Table 2, the formation of ketone 4a via ring-opening of
isoxazole ring was suppressed less than 7% yield.
Next, the scope of 5-bromoisoxazole 1 was investigated thor-
ough coupling reaction with phenylboronic acid 2a (Scheme 2).
Interestingly, the corresponding ring-opening products 4 were
not observed in all cases. With a benzyl group as R2, 3-(hetero)aryl
isoxazoles 3 k-m were obtained in good to high yields (64–77%).
Not only those 3-aryl isoxazoles, but also the 3-alkyl isoxazole
3n was provided in 92% yield. Substituents on a benzyl group did
not show any drastic effects, and the product 3o was obtained in
64% yield. Finally, methyl or n-propyl group on the C4-position also
gave the products 3p and 3q in good yields (84% and 52%,
respectively).
Scheme 1. Suzuki-Miyaura cross-coupling of the isoxazoles at the C5 position.
ligands resulted in low conversion of 1a with a poor yield of 3a
(entry 3, 13% yield). In contrast, the combination of Pd2(dba)3
and P(t-Bu)3ꢀHBF4 [12] gave only traceable amount of ketone 4a,
though approximately 40% of substrate 1a was recovered (entry
4). With this promising palladium salt and ligand system, various
solvents were investigated (entries 5–7 and see supporting infor-
mation, Table S1). As a result, the combination of K2CO3 and DMF
was found to be the best condition, and the trisubstituted isoxazole
3a was obtained in 88% NMR yield (73% isolated yield) while sup-
pressing the formation of ketone 4a in 5% yield. (entry 7). Next,
various phosphine ligands were examined (entries 8–16). Among
them, bulky ligands such as P(o-Tol)3 was found to exhibit an effi-
cient catalytic activity to afford 3a in high yield (entry 10, 87%
yield) accompanied by 6% yield of ketone 4a.
Conclusion
In this study, we succeeded in the Suzuki-Miyaura cross-cou-
pling of 3,4-substituted 5-bromoisoxazoles 1 at C5 position by
optimization of reaction conditions, giving trisubstituted isoxa-
zoles 3 while suppressing the formation of ketone 4 as a byproduct.
The use of bulky phosphine ligand P(t-Bu)3ꢀHBF4 is essential for the
Table 1
Optimization of the Suzuki-Miyaura cross-coupling reaction for the synthesis of 3a.a
Entry
Catalysts
Base
Solvent
Recovery of 1a (%)b
3a (%)b
4a (%)b
1
2
3
4
5
6
7
8
Pd(PPh3)4
Pd(PPh3)4
Pd(OAc)2
Na2CO3
K3PO4
K3PO4
K3PO4
K3PO4
Na2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
15
0
62
39
0
9
0
0
0
0
9
0
0
0
0
0
0
67
13
40
77
80
22
24
8
trace
2
5
5
6
4
6
6
5
8
5
10
17
Pd2(dba)3, P(t-Bu)3ꢀHBF4
Pd2(dba)3, P(t-Bu)3ꢀHBF4
Pd2(dba)3, P(t-Bu)3ꢀHBF4
Pd2(dba)3, P(t-Bu)3ꢀHBF4
Pd2(dba)3, PCy3
Pd2(dba)3, P(CH2CH2CH3)3
Pd2(dba)3, P(o-Tol)3
Pd2(dba)3, P(OPh)3
Pd2(dba)3, JohnPhos
Pd2(dba)3, XPhos
Pd2(dba)3, Xantphos
Pd2(dba)3, DPEphos
Pd2(dba)3, dppf
88 (73)c
68
79
87
17
50
77
75
78
57
9
10
11
12
13
14
15
16
a
b
Reagents and conditions: 1a (0.10 mmol), 2a (0.12 mmol), Pd-catalyst (10 mol%), ligand (20 mol%), base (0.40 mmol), solvent (2 mL), 16 h. NMR yield using 1,1-
dibromomethane as an internal standard. c Isolated yield in parenthesis. Ph = phenyl, Bn = benzyl, Ac = acetyl, dba = dibenzylideneacetone, Bu = butyl, THF = tetrahydrofuran,
DMF = N, N-dimethylformaldehyde, Cy = cyclohexyl, Tol = tolyl, JohnPhos = (2-biphenylyl)di-tert-butylphosphine, XPhos = 2-dicyclohexylphosphino-20,40,60-triisopropyl-
biphenyl, Xantphos = 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene, DPEphos = bis[2-(diphenylphosphino)phenyl] ether, dppf = 1,10-bis(diphenylphosphino)ferrocene.
2

M. Tsuda, T. Morita and H. Nakamura
Tetrahedron Letters 75 (2021) 153185
Table 2
Suzuki-Miyaura cross-coupling of 3a with various aryl boronic acids.
Entry
2
Ar
Yield (%)
3a
4ab
1
2
3
4
5
6
7
8
9
10
2a
2b
2c
2d
2e
2f
2g
2h
2i
phenyl
4-CH3C6H5
4-ClC6H5
4-CF3C6H5
3,5-CF3C6H3
4-CHOC6H5
4-CH2 = CHC6H5
4-pyridyl
73
84
56
72
52
61
43
54
57
92
5
5
3
6
5
4
trace
2
7
5
2-thienyl
2-naphtyl
2j
a
Isolated yield.
b
NMR yield using 1,1-dibromomethane as an internal standard.
Appendix A. Supplementary data
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.tetlet.2021.153185.
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The authors declare the following financial interests/personal
relationships which may be considered as potential competing
interests: Taiki Morita reports financial support was provided by
Japan Society for the Promotion of Science (JSPS). Hiroyuki Naka-
mura reports a relationship with Japan Society for the Promotion
of Science (JSPS) that includes: funding grants. Hiroyuki Nakamura
reports a relationship with AMED that includes: funding grants.
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